TRAF3 as a powerful and multitalented regulator of lymphocyte functions

This review summarizes the current state of knowledge regarding the roles of the signaling adapter protein tumor necrosis factor receptor (TNFR)-associated factor 3 in regulating the functions of B and T lymphocytes. In B lymphocytes, TNFR-associated factor 3 inhibits signaling by TNFR superfamily receptors, Toll-like receptors, and interleukin-6R. In contrast, signaling to B cells by the virally encoded oncogenic protein latent membrane protein 1 is promoted by TNFR-associated factor 3. An important B cell-specific role for TNFR-associated factor 3 is the inhibition of homeostatic survival, directly relevant to the common occurrence of TNFR-associated factor 3 mutations in human B cell malignancies. TNFR-associated factor 3 was recently found to be a resident nuclear protein in B cells, where it interacts with and inhibits gene expression mediated by the cAMP response element-binding protein transcription complex, including expression of the prosurvival protein myeloid leukemia cell differentiation protein 1. In T lymphocytes, TNFR-associated factor 3 is required for normal signaling by the T cell antigen receptor, while inhibiting signaling by the interleukin-2 receptor. Cytoplasmic TNFR -associated factor 3 restrains nuclear factor-κB2 activation in both T and B cells. Clinical implications and future directions for the study of this context-dependent signaling regulator are discussed.